Colorectal cancer (CRC) is the third most common cause of cancer death in the USA. Germline mutations in the apc tumor suppressor gene, a key player in CRC development and an important component in the Wnt/β-catenin signaling pathway, are responsible for familial adenomatous polyposis (FAP). Up to 80% of tumors have nuclear accumulation of β-catenin due to inactivating mutations in the gene for adenomatous polyposis coli (apc). Mutations that result in constitutive activation of the Wnt/β-catenin signaling pathway can lead to cancer. Wnt(s) have diverse roles in regulating cell fate, proliferation, migration, and death. The APC protein forms a complex with Axin, casein kinase 1 (CK1α, and glycogen synthase kinase 3-β (GSK3-β), which normally phosphorylates β-catenin to target the protein for proteasomal degradation. Mutations or loss of apc in CRC prevent degradation of β-catenin and subsequently lead to constitutive pathway activation. β-catenin binds to the T-cell factor-4 (Tcf-4) in the nucleus and thereby regulates transcription of genes related to growth, development, and differentiation of colonic cryptal cells. Accumulation of cytoplasmic and nuclear β-catenin, which may result from mutations in apc, β-catenin, or axin genes, or from activation of the Wnt signaling pathway, are key in CRC. Since the first report showing that Wnt signaling regulates the stability and translocation of β-catenin the detection of nuclear β-catenin in both laboratory models and in patient tumors has been widely used as a biomarker for demonstrating activation of the Wnt/β-catenin pathway.
Normally, in the absence of Wnt signaling, cytoplasmic β-catenin levels are kept at low levels through a continuous proteasome-mediated degradation by the “destructive complex” comprised of APC, glycogen synthase kinase3-β (GSK3-β), casein kinase 1 (CK1) and Axin. When cells receive Wnt signals, the degradation of β-catenin is suppressed and β-catenin levels build up in the cytoplasm and nucleus. Nuclear β-catenin interacts with the T-cell factor/lymphoid enhancer-binding factor (Tcf/Lef) transcription factor and acts as a transcription regulator for various genes that partially control tumor formation and progression. Once in the nucleus, constitutive activation of β-catenin/Tcf-4 mediates transcription of nuclear target genes.
Familial adenomatous polyposis is an inherited disorder in which patients develop polyps in the colon and rectum. Truncations in APC promote abnormal activation of Wnt/β-catenin signaling and lead to adenomatous lesions and are the most frequent cause of FAP. Mutations in β-catenin and apc are observed in many tumor types, suggesting that deregulation of Wnt/β-catenin signaling is important in the development of cancers. Notably, aberrant Wnt/β-catenin signaling following the loss of APC appears to initiate colon adenoma formation. Nuclear β-catenin was detectable in mouse models exhibiting loss of apc and transgenic mice with stabilized mutant β-catenin developed intestinal adenomas. Overall, studies suggest that deregulation of Wnt/β-catenin is a key oncogenic event that follows the loss of apc.